infections Susanne Matthes-Martin, Tobias Feuchtinger, Peter Shaw, - PowerPoint PPT Presentation

Management of adenovirus (ADV) infections Susanne Matthes-Martin, Tobias Feuchtinger, Peter Shaw, Dan Engelhard, Per Ljungman

ADV: Definitions I • Primary infection: First infection in infancy and childhood • Reactivation: Endogenous reactivation in immunocompromized patients • Reinfection: Infection with a new subtype. • Systemic infection / viremia: Positive PCR, virus isolation or Ag detection in blood • Local infection: Positive PCR, virus isolation or Ag detection in body fluids.

ADV: Definitions II • Probable disease Infection plus symptoms and signs without histological confirmation • Detection of ADV in stool + enteritis • Detection of ADV in urine + nephritis • Detection of ADV in PB + - fever together with negative - enteritis diagnostic tests - hepathopathy indicative for bacterial - nephritis or fungal infection • Proven disease: Infection plus symptoms related to the infection and histological confirmation • Detection of ADV in organ biopsy • Detection of ADV in cerebrospinal fluid • Multiple organ failure, high viral load in PB and detection of ADV in autoppsy

ADV Infection: high risk patients Children: • allo-SCT with in-vivo or ex-vivo T-cell depletion • allo-SCT with unrelated donor graft • allo-SCT with unrelated cord blood graft • severe (Gr III-IV) Graft versus Host Disease • severe lymphopenia (< 300 CD3+ cells/µl PB) Adults: • post allo-SCT haploidentical donor or unrelated cord blood graft • severe (Gr III-IV) Graft versus Host Disease • treatment with Alemtuzumab

ADV Infection in the immunocompromized host: sings and symptoms • Fever • Enteritis • Hepathopathy • Nephritis • Retinitis • Encephalitis

Recommendation ADV: diagnostic techniques • PCR is fast and has higher sensitivity and specificity compared to culture or IF (AII) • Quantitative PCR is more predictive for lethal disease (AII) • Quantification in stool samples helps to identify patients (primarily children) at risk for viremia (BIII) • Subtyping of adenovirus might yield additional information • Quantitative PCR - either commercial or in-house (validated by round-robin tests) is the current gold standard and should be used (A II)

ADV: diagnostic studies • High incidence of ADV-infection post allo-SCT in children • Low incidence of ADV-infection post allo-SCT in adults. • Incidence increases with degree of immunosuppression both in adults and children • High mortality in case of ADV-viremia • ADV infection is a rare event following autologous SCT • No screening studies available for children with chemotherapy • Single cases of lethal ADV hepatitis in children with ALL

Recommendation ADV-screening in allo SCT (children): • Quantitative PCR-screening on PB is recommended on an at least weekly basis to patients at risk (AII) • Screening is not routinely recommended in patients receiving matched sibling grafts (BII) • Length of screening should be adapted according to degree of immune reconstitution (BIII) Recommendation ADV-screening in allo SCT (adults): • Routine screening is not routinely recommended in standard risk patients (BII) • For high risk patients screening should be considered (BIII) • Length of screening should be adapted according to degree of immune reconstitution (CIII)

Recommendation ADV-screening in auto SCT and chemotherapy: • no viral screening warranted (BII) • quantitative PCR in case of clinical suspicion (BIII) Recommendation ADV-monitoring in case of viremia: • In patients with ADV-viremia viral load should be monitored by quantitative PCR at least once weekly (AII)

ADV: Prophylactic virostatic treatment No data on cidofovir or ribavirin Ganciclovir: Bruno et al 2003 lower incidence of ADV infection in patients receiving prophylactic ganciclovir Avivi et al 2004 trend towards lower incidence Recommendation prophylactic treatment: Prophylactic antiviral therapy is not recommended (BIII)

ADV recommendation for preemptive treatment of asymptomatic viremia: Goal: To prevent ADV disesase Indication to start preemptive treatment: ADV viremia plus presence of at least one risk factor (BII) Children: • allo-SCT with in-vivo or ex-vivo T-cell depletion • allo-SCT with unrelated donor graft • allo-SCT with unrelated cord blood graft • severe (> Gr II) Graft versus Host Disease • severe lymphopenia (< 300 CD3+ cells/µl PB) (BIII) Adults: • post allo-SCT haploidentical donor or unrelated cord blood graft • Gr III-IV acute Graft versus Host Disease • following treatment with Alemtuzumab Viral loads should be monitored during therapy (BIII)

ADV recommendation for treatment indication: Indication to start treatment: (BIII) - Proven ADV disease - Probable ADV disease

Adenovirus – treatment options • Antiviral drugs • Cidofovir • Ribavirin • Ganciclovir • CMX001 (oral lipid derivate of cidofovir; non-licensed) • Other options • Iv Ig • Transfer of adenovirus specific T-cells (experimental) • Reduction/withdrawal of immunosuppression

ADV recommendation for treatment I: • Iv. cidofovir is recommended as first line therapy (BIII) • Studies of preemptively given cidofovir suggests efficacy in reducing viral load • No clear data to support that preemptive cidofovir reduces the incidence of ADV disease • No clear data regarding efficacy in treating adenovirus disease • Varying doses and schedules have been used most commonly 5 mg/kg weekly (2-3 doses) thereafter every other week. There is no evidence supporting one particular schedule • Supportive measures should be taken with oral probenecid hyperhydration, and if possible avoidance of other nephrotoxic drugs at day of cidofovir administration (BIII)

ADV recommendation for treatment II: • Ribavirin is not generally recommended for adenovirus infection but can be considered in cases with type C infections especially in patients with decreased renal function (CIII) • Consider the addition of iv Ig (BIII) • Immunosupression should be reduced whenever possible (AII) • For systemic adenovirus disease, virus specific CTLs can be considered if available (B III)

Future developments • Lower risk for ADV-associated disease and ADV-associated mortality has been shown in the presence of ADV-specific T-cells • Safety and feasibility of adenospecific T-cell transfer has been shown (Feuchtinger et al BJH 2006; Leen et al, Nature Medicine 2006) • Adenospecific T-cell transfer is a promising strategy but there are still limited data on efficacy and further studies are neded (Leen et al Blood 2009; Feuchtinger et al. 2009) • Multispecific CTLs are in development • CMX001, a cidofovir lipid conjugate, has shown efficacy in a phase II study